Inflammation and prediction of death in type 2 diabetes. Evidence of an intertwined link with tryptophan metabolism

Abstract Context The role of inflammation in shaping death risk in diabetes is still unclear. Objective To study whether inflammation is associated with and helps predict mortality risk in patients with type 2 diabetes. To explore the intertwined link between inflammation and tryptophan metabolism on death risk. Methods There were 2 prospective cohorts: the aggregate Gargano Mortality Study (1731 individuals; 872 all-cause deaths) as the discovery sample, and the Foggia Mortality Study (490 individuals; 256 deaths) as validation sample. Twenty-seven inflammatory markers were measured. Causal mediation analysis and in vitro studies were carried out to explore the link between inflammatory markers and the kynurenine to tryptophan ratio (KTR) in shaping mortality risk. Results Using multivariable stepwise Cox regression analysis, interleukin (IL)-4, IL-6, IL-8, IL-13, RANTES, and interferon gamma–induced protein-10 (IP-10) were independently associated with death. An inflammation score (I score) comprising these 6 molecules is strongly associated with death in both the discovery and the validation cohorts HR (95% CI) 2.13 (1.91-2.37) and 2.20 (1.79-2.72), respectively. The I score improved discrimination and reclassification measures (all P < .01) of 2 mortality prediction models based on clinical variables. The causal mediation analysis showed that 28% of the KTR effect on mortality was mediated by IP-10. Studies in cultured endothelial cells showed that 5-methoxy-tryptophan, an anti-inflammatory metabolite derived from tryptophan, reduces the expression of IP-10, thus providing a functional basis for the observed causal mediation. Conclusion Adding the I score to clinical prediction models may help identify individuals who are at greater risk of death. Deeply addressing the intertwined relationship between low-grade inflammation and imbalanced tryptophan metabolism in shaping mortality risk may help discover new therapies targeting patients characterized by these abnormalities.